1. Field of the Invention
The invention relates to the use of NADH and NADPH as therapeutic agents, and particularly to administering NADH and NADPH nasally, sublingually, rectally and topically to the skin for a variety of therapeutic effects.
2. Description of Related Art
Nicotinamide-adenine-dinucleotide in its reduced form ("NADH") and nicotinamide-adenine-phosphate-dinucleotide in its reduced form ("NADPH") are physiological substances which occur in all living cells including human cells. These substances are cofactors for a variety of enzymes, the majority of which catalyze oxidation-reduction reactions. Prior to recent discoveries as to the therapeutic properties of these compounds, their principal utility has been as diagnostic tools in clinical biochemistry and as essential components in reaction kits, for example, in measuring lactatdehydrogenase (LDH).
The most important function of NADH is its driving force for cell respiration. When using oxygen, NADH forms water and 3 ATP molecules in accordance with the following formula: EQU NADH+H.sup.+ +1/20O.sub.2 +3Pi+3ATP.fwdarw.NAD.sup.+ 3AT+4H.sub.2 O.
Thus, with 1 NADH molecule, 3 ATP molecules are obtained which have an energy of approximately 21 kilocalories. This process is called oxidative phosphorylation. The supply of NADH and/or NADPH makes this work much easier for the organism, because it has greater energy reserves as a result.
More recently, NADH and NADPH and pharmaceutically acceptable salts thereof have been shown to be useful in the treatment of Parkinson's Disease. The effectiveness of these agents for this purpose is documented in my existing U.S. Pat. Nos. 4,970,200 and 5,019,561, the disclosures of which are incorporated herein by reference.
In addition, I have discovered that these substances are effective in the treatment of Morbus Alzheimer (i.e., Alzheimer's Disease), which is the subject of my U.S. Pat. No. 5,444,053 as well as in the treatment of mental depression, which is the subject of my German Patent DE 410361.
Prior to my recent discoveries, NADH and NADPH have never been considered for therapeutic use, probably because it was believed that these compounds are rather unstable and, hence, not capable of being absorbed by the intestines of the human body. It would have been expected that these substances would be hydrolized in the plasma within a few seconds.
However, studies performed recently using NADH and NADPH demonstrate that these assumptions are incorrect. When NADH and NADPH were applied intravenously to patients with Parkinson's disease, a remarkable beneficial effect was observed which lasted at least 24 hours. See U.S. Pat. Nos. 4,970,200 and 5,019,561. This indicates that NADH and NADPH are not rapidly degraded in the plasma and blood.
One drawback to intravenous application of NADH and NADPH is that it requires an injection which has to be performed in a hospital or at the physician's practice. This requirement can be inconvenient or demanding on the patient's schedule. Therefore, it would be desirable to find another form for NADH and NADPH which would allow patients to take these substances regularly under their own supervision.
My U.S. Pat. No. 5,332,727 teaches a stable, ingestable and absorbable NADH and/or NADPH therapeutic composition which can be taken orally. It was discovered that this oral form is absorbed by the intestine, and is effective in the treatment of Parkinson's disease and Alzheimer's disease. However, it would also be desirable to administer NADH and NADPH in ways other than orally and intravenously for a variety of therapeutic effects.
For example, my copending application Ser. No. 08/122,035 filed on Sep. 15, 1993 teaches that NADH and NADPH are effective in the treatment of Alzheimer's disease when administered orally or intravenously. However, it would also be desirable to administer the NADH or NADPH intranasally, since nasal administration has proven to be a direct and effective way to deliver neurologic agents to the brain (see International Publication No. WO 91/07947). The olfactory neural pathway is a route for delivering neurologic agents to the brain which circumvents the bloodstream, and thereby avoids the need for the agent to traverse the blood-brain barrier.
It has also been discovered that the mitochondria play a major role in cell degeneration. Recent studies suggest that modifications of mitochondria leading to their uncoupling are harmful to cells, and are responsible for some of the degenerative processes involved in natural or externally induced cell death. It has been observed that the inactivation of mitochondria results in diminished ATP production which adversely affects cellular homeostasis, thereby leading to cell degeneration. See Corbisier, P. et al. "Involvement of Mitochondria in Cell Degeneration" in European Journal of Cell Biology, Vol. 51, pp. 173-182 (1990). Corbisier et al. have suggested that if the observed cellular degeneration was due to an intracellular energy decrease caused by inactivation of the mitochondria, a source of energy for endogenous mitochondria should counteract the NADH depletion. Corbisier et al. discovered that a readily metabolized energy source, namely D(--)-.beta.-hydroxybutyrate sodium salt, inhibited cell degeneration resulting from the presence of uncoupled mitochondria in a dose dependent manner.